Basic side chain substituted quinoline derivative



Patented Oct. 18, 1949 v 2,485,174

UNITED STATES PATENT OFFICE BASIC SIDE CHAIN SUBSTITUTED QUINOLINEDERIVATIVE Dean S. Tarbell, Rochester, and Nancy Shakespeare, PortWashington, N. Y., and Joseph F. Bunnett, Iortland, reg., assignors, bymesne assignments, to the United States of America as represented by theSecretary of War.

No Drawing. Application April 8, 1946,

Serial No. 660,418

2 Claims. (01. 260-288) 2 The present invention relates to a novel classvention is to provide a new and improved class of compoundscharacterized by superior antiof synthetic antimalarial drugs.

malarial P p and to ods of preparing A more specific object is theprovision of a the same. novel class of 4-aminoquino1ine compounds hav-Within the past several years, interest in the 5 ing suppressiveantimalarial properties approxisynthesis of antimalarial drugs has beengreatly mately equivalent to, or possibly somewhat stimulated by therecently reported therapeutic greater than, those of SN 7618, butcharacterized properties of certain members of the acridine, the by asignificantly lower toxicity to the host or -aminoquinoline and the8-aminoquino1ine patient. I classes; notably6-chloro-2-methoxy-9-(5-dieth- Another object is to provide suitablemethods ylaminopenty1-2-amino)acridine or quinacrine; for thepreparation of such drugs from readily7-chloro-4-(5-diethylaminopentyl-2-amino) quinavailable raw materials.oline or SN 7618; and 8-(5'-isopropylamino- Other objects and advantageswill be apparent pentylamino) 6 methoxy quinoline or SN as thedescription progresses. 13276. It has been discovered, in accordancewith the present invention, that the foregoing objects may CH beattained by the synthesis of compounds of the a general type I N -(0:)i- (C2 s): CEO 2 NH-(CH h-NH alkyl 01 N X Quinacrine \N CH1NHtJHwHmNwiHi): wherein X is a nuclear substituent such as halogen( forexample, chlorine) located preferably in position 7. Compounds of thistype are highly active suppressive antimalarial drugs, being N roughlyequivalent in this respect to SN 7618,

but are characterized by significantly lower tox- SN 7618 icity than SN7618. Surprisingly enough, the

corresponding dialkylaminopropyl amino compounds of type II 011,0

N NIH-(0H,) a-N (alkyl):

NH-(CHflu-NHCH-(CHO: SN 13210 x The outstanding therapeutic propertiesof quin- N acrine, SN-7618 and SN-13276 relative to quinine 11 in thetreatment of certain types of malaria has led to an intensivere-examination of other synare either less active as antimalarials ormore thetic compounds in the hope that even more toxic than SN 7618, orboth.

efiective drugs might be developed. The compounds of the presentinvention (I) Broadly stat d, he Qbj Q the present inmay be readilyprepared by condensing the ap- 3 propriate diamine (III), with a4,7-dihaloquinoline such as 4,7-dich1oroquinoline (IV) 01 HzN(CHz)3-NHAlkyl III The diamines (III) may be prepared conven= iently by themethod of Holcomb and Hamilton [J. Am. Chem. Soc. 64, 1309 (1942)] whichconsists in addition of an amine to acrylonitrile, fol

This reaction has usually been applied to secondary amines, but Whitmoreet al. [J. Am. Chem. Soc. 66, 725 (1944)] made the compound fromethylamine, and there are a few scattered references in the patentliterature to addition of primary amines to acrylonitrile, although theproducts are not well characterized.

The addition of the primary amines to acrylonitrile goes smoothly,without use of a catalyst, and our observations support Whitmoresstatemerit that the addition is an equilibrium reaction. Event-butylamine adds to acrylonitrile, although in somewhat lower yieldthan amines with a primary or secondary alkyl group.

The reduction of the nitriles (V) were carried out in the presence of acatalyst (for example,

Raney nickel) under pressure (e. g.-, about 2500 lbs.) and at elevatedtemperatures (e. g., about 100-120 C.) preferably using alcoholsaturated with ammonia to repress the formation of secondary amine. Thereduction is usually complete in about fifteen minutes and the yieldsare good. The reaction of the di amines (III) with 4,7-dichloroquinoline (IV) proceeded with vigorous evolution of heat at atemperature of the order of about 150160 C.

The foregoing general method may be applied to the preparation of a widevariety of compounds of the type (I). In order still more clearly todisclose the nature of the present invention, a specific example of theprocedure used for the preparation of one embodiment will hereinafter bedescribed in considerable detail. It should nevertheless be understoodthat this is done solely by way of example and not for the purpose 'ofdelineating the breadth of the invention or limiting the ambit of theappended claims.

EXAMPLE Experimental procedures are similar for all the compounds ofthis type (I) and are illustrated for the n-butyl series; physicalproperties and analyses for the n-butyl compounds as well as a number ofother related compounds are given in the Various tables below. Allmelting points are corrected. Temperatures are given in degreesCentigrade throughout the present case.

n-Butylaminopropionitrile (VR.=n-C4H9) Acrylonitrile (24.2 g.) was addeddropwise with stirring during ninety minutes to 50 g. of nbutylamine,the temperature being kept below 4 30 C. by a cold-water bath. Stirringwas continued for five hours after the addition was complete, themixture was then refluxed on the steam bath for ninety minutes andallowed to stand overnight. Vacuum distillation of the mixture yielded55.4 g. (98%) of n-butylaminopropionitrile.

The phenylurea derivatives were best prepared by adding 1 cc. ofphenyl-isocyanate to 1 cc. of the nitrile dissolved in 10 cc. ofpetroleum ether; there was a vigorous reaction, and the product, if notcrystalline immediately, became so on standing in the ice-box. Thecompounds were recrystallized from methanol-water or benzenepetroleumether.

'y-n-Butylaminopropylamine (III, A1kyl=n-C4H9).-n-Butylaminopropionitrile (40 g.) was reduced in 150 cc. ofalcohol saturated with ammonia, using Raney nickel at 120 C. and 2500lbs. of hydrogen; the reduction was complete in about fifteen minutes.The catalyst was removed by filtration, most conveniently with the useof Super Filtrol, and the alcohol fractionated through a Vigreux column;27.2 g. (66%) of the n butylaminopropylamine was obtained. Yields forthe reduction of the other nitriles ranged from about 55% to 70%.Analytical samples of the products of this and the preceding paragraphwere obtained by fractionation in a small column under reduced pressure.

7 chZoro-4 3- n butylaminopropylamino) quinoline (I, Alkyl=n-C4H9;X=7-C1) .-n-Butylaminopropylamine (24.7 g.) and 17.8 g. of 4,7-dichloroquinoline were placed in a 250 cc. threeneck flask fitted with acondenser and a mercuryseal stirrer, and heated in an oil bath at about155 C. After about fifteen minutes, a vigorous exothermic reactionoccurred and it was necessary to cool the flask quickly with an icebath. After the reaction had subsided, heating at about 155 C. wascontinued for five hours. An excess of 6 N sodium hydroxide was addedand copious yellow precipitate formed. The mixture was steam distilleduntil the odor of amine was no longer detectable in the distillate. Thesolid material was removed and washed with Water. It was then dissolvedin hot acetone, treated with anhydrous sodium sulfate and Norite, andfiltered. The crystals which formed on cooling melted at 91-101 C. Fourrecrystallizations from acetone yielded 13.4 grams (51.3%) of 7-chloro-4-(3-n-butylaminopropylamino) -quinoline, M. P. 100-103.5 C.

The other quinoline bases were likewise purified by repeatedrecrystallizations from acetone, in which 4,7-dichloroquinoline is verysoluble; other solvents proved less useful.

7-chlor0- 4 -(3 n butylaminopropylami'no quinolinemonosulfate.7-chloro-4-(3-n-butylaminopropylamino)-quinoline (21.7 g.)was dissolved in 100 cc. of absolute alcohol and 23 cc. of 6 N H2804 wasadded with cooling, which formed a copious white precipitate of themonosulfate. Water (65 cc.) was added so that all the solid was insolution at the boiling point of the mixture. On cooling, themonosulfate was again precipitated. This was recrystallized four timesfrom a mixture of 75 cc. of alcohol and 50 cc. of water. The purifiedcompound was dried at about C. in an oven overnight and yielded 20.5 g.(72.7%) of the dry monosulfate.

The following are the ratios of alcohol: water used to recrystalli'zethe various compounds:

CH3, 35:30; C2H5, 75:30; n-C3H7, 65:30; i-C3H7, 50:30; s-C4H9, 45:30;t-C4I-I9, 20:30.

TABLE I p-Alkylwminopropionitriles, RNHCI-IzCHaCN Yield, B a C m Oalcd.Found Per Cent P., no I ormula O H O H 1 71 101-104 (49 mm.) L 1. 4320C4H3Nz 2 84 97-98 (30 mm.) 1. 4333 G fi Nzu 3 92 119-121 (30 mm.) 1.4362 05H1$N2 64.22 10.80 64.13 10.71 4 98 104-106 rnm.) 1. 4392 C1H14 z66. 62 11.20 66.48 11.28 5 83 92-96 (10 mm.) 1. 4379 .fl 6 t-CrHa 5681-83 (10 mm.) 1.4329 do 66. 62 11.20 66. 60 11.37 7 00 11 (Cyclohexy 92122-124 (4 mm.) 1.4764 CQHHNZ--- 70. 98 10.61 71. 03 10. 52

e In the preparations of methyland ethylaminopropionitrile, 33% amine inwater was used instead of the pure amine. After standing overnight, 150g. of anhydrous potassium carbonate was added for every 180 g. of waterpresent, and the mixture was shaken until all the solid had dissolved.The organic layer was then distilled to yield the desired product.

A. H. Cook and. Reed, J. Chem. Soc., 399 (1945) report B. P. 74 (16111111.); 17.9 1.4342.

c Whitmore et a1. (supra) report 13. P. 9295 mm.); n9 1.4318.

d French Patent 742, 358 (O. A., 27, 3483 (1933)) reports a B. P. of114-116 (20 mm.); German Patent 598, 185 (O. A., 28, 5474 (1934) givesit as 114116 (12 mm.). No other information is given.

' Cope, private communication, reports B. P. 95 (13.5 mm.); ma 1.4340. u

1 French Patent 742, 358 (C. A... 27, 3483 (1933)) reports 13. P.149-151 (11 mm.) The same value is given in German Patent 598, 185 (C.A., 28, 5474 (193 4)).

TABLE II Phenylurea derivatives, RNCHBCHQCN CONHCaHs Calcd. Found R M.P., 0. Formula C H O H 93.5- 94.5 O11H13N30 65.00 6 64. 91 6.54 81. 5-82 CiaHnNsO- 67. 7. 41 67. 46 7. 28 126 -126. 5 d0 67.50 7.41 68. 027.39 132. 5-134 CuHwNaO.- 68. 53 7. 81 68. 62 7. 66 SC4Ha 127. 5-128. 5d0 68. 53 7. 81 68. 54 7. 76

TABLE III -Alkylarninopropylamines,

RNHCHzCHzCH NHz Dipimte Oaicd. Found R B. P., C. m) M. P., 0. Formula CH C H 1 1. 4479 n 224. 5-226. 5 2 1.4455 191 193 3 1.4460 166. 5167.5C1aHz2Na0i4 37.63 3.86 37.48 3 89 4 1.4433 185 186.5 do 37.63 3.86 37.933.73 5 1.4490 -151 HzaNaOu... 38.77 4.11 38.67 4.10 6 l. 4480 166 do-38.77 4.11 38.63 4.18 7 1.4431 216 -217 38.77 4.11 38.87 3.80 8 1.4820182. 5-1835 41.04 4.26 41.05 4.29

I v. Braun et al., Ber., 70, 979 (1937) report B. P. 138-139; M. P. ofpicrate 227.

b Whitmore (supra) reports B. P. 156 (735 mm.); up 1.4441; M. P. ofpicrate 193".

e Anal. of diamine: Calcd. for oaH oNzl C, 62.01; H, 13.91. Found: C,61.99; H, 13.81.

4 Cope, private communication, reports 13. P. 161-162"; no 1.4394.

= Anal. of diamine: Calcd. for C7H1sN2Z O, 64.52; H, 13.95. Found: C,64.61; H, 13.75. German Patent 598, (C. A.,

28, 5474 (1934)) reports B. P. 60 (1 mm.).

f Cope, private communication, reports B. F. 72 (13.5 mm.); no" 1.4427.

2 Anal. of diamine: Calcd. for G1H1iNz: O, 64.52; H, 13.95. Found: C,64.62; H, 13.81.

11 Anal. of diamine: Calcd. for CQHzoNzZ C, 69.16; H, 12.92. Found: 0,69.10; H, 12.90.

TABLE IV 7-chloro-4-alkylaminopr pylaminoquinolines NHCHaCHaCHaNHBCalcd. 7 Found 7 Formula 0 O H O H 1 O ;H1 N3O1O (monohydrate)-- 58.296.79 59.06 6.58 2 O14HzuClNaO (monohydrate). 59.67 7.15 60.67 7.47 301511200111. 64. 87 7. 27 64. 78 7. 43 4 C15H22C1N3O 6 (monohydtateL.60.89 7. 51 60.93 7. 47 5 CmHzzClNa d 65. 84 7. 61 64. 82 7. 08 6G1aH22ClNs 65. 84 7. 61 64. 50 7. 13 7 do 65.84 7.61 65.94 7.34 8CHHMGINI) 68. 01 7. 63 67. 91 7. 54

e Temperature of oil bath during coupling was 135.

b Neut. equiv., calcd. for monohydrate, 140.9. Found (from titrationcurve), 142.3. Cope, private communication, reports M. P. 107.5108 G.for the anhydrous base. 6 Neut. equiv., calcd.: 145.9. Found (fromtitration curve) 157.

TABLEV 7-chloro-4-allcylaminOpropylaminoquinoline monosulfates Molecularb Calcd. '7 Found 7 R OP; weight Found Formula 0 o 08106.. O I H O I H 1CH 347.9 340.3 G13H1QCIN304S... 44.37 5.23 44.40 5.40 2 02H. 361.8 362.8C14H20C1N3O4S 46.45 5.57 46.76 5.69 3 11-0311 375.3 371.2 OH2zOlNaO4S47.94 5.91 47.75 0.05 4 1-04111 375.3 370 do 47.94 5.91 43.03 0.01 511-01 339.3 393.4 C|6H24C1N304s 49.23 0.22 43.93 0.35 6 3-0411." 339.3394.6 .do 49.23 0.22 43.71 5.19 7 t-O4H9 250-252 194.9 201.0 d0 49.230.22 49.25 5.47 3 O0H11(Oy010hexyl) 310-315 203.0 214.5 C 3H20O1NaO4S51.97 0.31 52.10 0.57

a All of the salts melt with decomposition.

b Molecular weights obtained by doubling the neutralequivalent, o

d Sample dried to constant weight at 140 in vacuo.

In order to illustrate the therapeutic advantages of the compounds ofthe type (I) in accordance with the present invention, test data, for 7-chloro-5- (ethylaminopropylamino) quinoline may be taken asrepresentative. This particular compound (SN 13,588), on the basis oftests against gallinaceum in the chick, is roughly four times as activeas SN 7618. On the basis of toxicity tests in the mouse, the rat and thedog, SN 13,588 is, respectively, 0.4, 0.5 and 0.25 as toxic as SN 7618,and in the monkey, the data indicate that SN 13,588 is also less toxicthan is SN 7818, although in this test subject the relative values havenot as yet been quantitatively determined. It is therefore apparent thatSN 13,588 is no less effective as a suppressive antimalarial than SN7618 and also that it is much less toxic to the host than is theparticular reference compound.

It will be apparent to those skilled in the art that many variations maybe made in the procedure described in the example, without departingfrom the basic principles involved. All such variations, modificationsor extensions are to be understood as included within the scope of theappended claims.

We claim:

1. A new series of compounds composed of the group consisting of thefree bases having the structural formula Halogen- N 2. The compounds ofclaim 1 wherein the halogen radical consists of a chloro group.

DEAN S. TARBELL. NANCY SHAKESPEARE. JOSEPH F. BUNNETT.

REFERENCES CITED The following references are of record in the file ofthis patent:

Whitmore et al: Journal Amer. Chem. Soc., vol. 66, pp. 725-731 (1944).

